Evidence-based pharmacotherapy for attention-deficit hyperactivity disorder

There is a substantial body of literature documenting the efficacy of multiple unrelated pharmacological agents in attention-deficit hyperactivity disorder (ADHD) individuals throughout the life-cycle. The available literature indicates the important role of psychopharmacological agents in the reduction of the core symptoms of ADHD and associated impairments. The literature documents that stimulants not only improve abnormal behaviours of ADHD, but also improves self-esteem, cognition, and social and family function. However, response varied in different age groups and with certain comorbidities. In addition there is a large body of literature documenting the efficacy of atomoxetine which shows improvement in these same domains. More research is needed on alternative pharmacological treatments and to further evaluate established therapeutics beyond school-aged Caucasian boys. Further, more research is needed on the efficacy of treatment for comorbid ADHD, use of combined medications, and the combination of medication and psychosocial treatment.     

Drugs under investigation for attention-deficit hyperactivity disorder

There has been substantial development of pharmacological treatments for attention-deficit hyperactivity disorder (ADHD) recently. The greatest change is the approval of new delivery systems for methylphenidate (MPH) and amphetamine (AMP) that permit once a day dosing. There are also a number of new compounds under development for the disorder, including several non-stimulant agents. These compounds target the noradrenergic, histaminergic and dopaminergic systems. The recent developments in the pharmacological treatment of ADHD should increase therapeutic options and the percentage of individuals with the disorder who can be effectively treated.     

Emerging drugs for attention-deficit/hyperactivity disorder

Symptoms of attention-deficit/hyperactivity disorder (ADHD) are heterogeneous and often accompanied by comorbid psychiatric disorders. Although symptoms tend to lessen with age, many patients continue to be affected by the disorder into adulthood. Although many medications are available to treat ADHD, it is unlikely that a single medication will ever be developed to work for all patients. Recent advances, such as long-acting, extended-release formulations and transdermal delivery systems, have lengthened the duration of effectiveness, which has increased compliance and eliminated the need for additional medication dosing during the school or work day. Additional safe, well-tolerated, long-acting medications with further reduced potential for diversion and abuse are needed. Catecholamine pathways and their effect on executive functions and ADHD symptom control have been productive areas of research. Potential therapies such as adrenergic receptor agonists, glutamatergic agents, GABA receptor antagonists and nicotine receptor agonists are being explored as future pharmacotherapies for ADHD.     

Substance abuse in patients with attention-deficit hyperactivity disorder : therapeutic implications

Attention-deficit hyperactivity disorder (ADHD) is a common disorder in children that frequently persists into adulthood. Studies have found that substance use disorders (SUD) are seen more commonly in those with ADHD than the general population. Although treatment with stimulant medications has been shown to be effective for individuals with ADHD, concern about the use of these agents in this population persists. This review article highlights the research in this area with a focus on the treatment of individuals who present with concomitant ADHD and SUD. Although stimulants can be abused, studies have shown that adolescents who are prescribed stimulants for ADHD have lower rates of SUD than those who are not treated with stimulants. It may be particularly difficult to evaluate adults for the diagnosis of ADHD when SUD is a co-morbid factor. Studies show that 20--30% of adults presenting with SUD have concomitant ADHD and approximately 20--40% of adults with ADHD have histories of SUD. Therefore, it is critical to perform careful diagnostic interviews to discern if patients have either or both of these disorders. Many clinical experts suggest that adults with ADHD and active SUD be treated for the SUD until a period of sobriety persists prior to initiation of specific treatment for ADHD. Since individuals with ADHD and active SUD are more likely to have more severe SUD and a worse prognosis, this approach may not serve many patients, as they relapse prior to obtaining ADHD treatment. Therefore, research has been directed towards determining if the treatment of ADHD with stimulant medications can be safe and effective for the individual with active SUD and concomitant ADHD. An initial trial of methylphenidate in a population of adults with active cocaine dependence and ADHD indicates that this is the case. Individuals with ADHD and SUD can present difficult diagnostic and therapeutic challenges. It appears that the most effective treatment option is to create a programme that uses the most effective treatment modalities available, including both behavioural and medical therapies, along with close supervision and monitoring. Newer medical treatment options of long-acting stimulants and non-stimulants (e.g. atomoxetine) offer effective treatment with a lower risk of abuse potential.     

Atomoxetine blocks motor hyperactivity in neonatal 6-hydroxydopamine-lesioned rats: implications for treatment of attention-deficit hyperactivity disorder

We recently reported that selective inhibitors of neuronal transport of norepinephrine (NE), desipramine and nisoxetine, reversed motor hyperactivity in an animal model of attention-deficit hyperactivity disorder (ADHD). In this study, we examined behavioural effects of atomoxetine, a potent new NE reuptake blocker, in juvenile male rats with neonatal 6-hydroxydopamine (6-OHDA) lesions of dopamine projections to the forebrain. 6-OHDA (100 microg) was administered intracisternally on postnatal day (PD) 5 following desipramine (25 mg/kg s.c.) pretreatment to protect noradrenergic neurons. Atomoxetine (1 mg/kg) was given intraperitoneally before recording motor activity for 90 min at PD 23-26 in a novel environment. Atomoxetine greatly reduced motor hyperactivity in 6-OHDA-lesioned rats while exhibiting transient sedative effects in sham controls. The observed effects in this animal model for ADHD are consistent with the emerging clinical use of atomoxetine as a novel, non-stimulant treatment for ADHD.     

Pharmacological management of attention-deficit hyperactivity disorder

Pharmacotherapy is the most common intervention for attention-deficit hyperactivity disorder (ADHD). Stimulant medications are highly efficacious and are the gold-standard for treating the inattention, impulsivity and excessive motoric activity associated with ADHD. Methylphenidate and amphetamine-based stimulants are now available in longer-acting, once-daily and shorter-acting divided dosing schedules. Several nonstimulant, second-line treatments are now available or under development for the treatment of ADHD in children and adults. This article reviews the support for a variety of pharmacological agents and the issues to be considered when selecting an agent. The authors conclude that there is a need for additional direct comparisons between the longer-acting agents to effectively guide the practicing clinician.     

Pharmacological management of attention-deficit hyperactivity disorder

Pharmacotherapy is the most common intervention for attention-deficit hyperactivity disorder (ADHD). Stimulant medications are highly efficacious and are the gold-standard for treating the inattention, impulsivity and excessive motoric activity associated with ADHD. Methylphenidate and amphetamine-based stimulants are now available in longer-acting, once-daily and shorter-acting divided dosing schedules. Several nonstimulant, second-line treatments are now available or under development for the treatment of ADHD in children and adults. This article reviews the support for a variety of pharmacological agents and the issues to be considered when selecting an agent. The authors conclude that there is a need for additional direct comparisons between the longer-acting agents to effectively guide the practicing clinician.     

Drug therapy for adults with attention-deficit hyperactivity disorder

Practitioners are increasingly called upon to diagnose and treat attention deficit hyperactivity disorder (ADHD) in adults. Although the use of pharmacotherapy in children with ADHD is well studied, the use of drugs for the treatment of adults with ADHD remains less well established.A systematic review of the literature identified 15 studies (n = 482 patients) of stimulants, and 27 studies of nonstimulant medications (n = 1179 subjects) including antidepressants, norepinephrine reuptake inhibitors, antihypertensive agents, amino acids and wake-promoting agents for the treatment of ADHD in adults.Controlled clinical trials in adults showed that stimulants, antidepressants and norepinephrine reuptake inhibitors demonstrated significant short-term improvements in ADHD symptoms compared with placebo. The two longer term trials with methylphenidate in adults confirmed the ongoing effectiveness and tolerability of stimulants. The response to amphetamine and methylphenidate appears to be dose-dependent. Methylphenidate and amphetamine had an immediate onset of action, whereas responses to pemoline, antidepressants and norepinephrine reuptake inhibitors appeared delayed. Controlled data on nicotinic/cholinergic compounds appear promising. Considerable variability was found in the diagnostic criteria for ADHD in adults, drug dosages and response rates between the various studies.Under controlled conditions, the aggregate literature comprised mainly of short-term studies, shows that stimulants, norepinephrine reuptake inhibitors and specific antidepressants had clinically and statistically significant beneficial effects in the treatment of ADHD in adults. Cholinergic agents appear promising. Further studies are necessary to evaluate the long-term effectiveness and tolerability of various agents, functional and neuropsychological outcomes, and the use of various agents in specific subgroups of adults with ADHD.     

Agents for attention-deficit hyperactivity disorder – an update

Attention-deficit hyperactivity disorder (ADHD) is a psychological disorder affecting children and adolescents, whose symptoms often persist into the adult years, and is often effectively treated with stimulants. Recently, non-stimulant medications that demonstrate better toleration and administration have been studied in clinical settings and some have been approved. Yet, there continues to be strong emphasis in many research groups to find even more efficacious and safer alternatives, especially with substances that function through novel, non-stimulatory mechanisms. A review of the progress achieved during the last 4 years, determined from the publication of patents and patent applications, is presented.     

Pozanicline for the treatment of attention-deficit/hyperactivity disorder

Introduction: Attention-deficit/hyperactivity disorder (ADHD) is the most common neurobehavioral disorder occurring in childhood and often continues into adolescence and adulthood. The pathophysiology of ADHD is complex and likely involves multiple neurotransmitter systems. Medications currently used for the treatment of ADHD enhance dopaminergic and/or noradrenergic transmission. However, none of these drugs target the cholinergic system, which is also thought to play a significant role in cognitive disturbances such as those found in ADHD.

Areas covered: In this review, the authors briefly discuss the cholinergic system, including multiple neuronal nicotinic receptor (NNR) subtypes that mediate the positive and negative effects of nicotine, in the context of animal models of ADHD. They also discuss the pharmacology of the NNR pozanicline, a partial agonist with high in vitro binding affinity and selectivity for the α₄β₂ NNR subtype. Finally, the authors examine pozanicline’s clinical developments.

Expert opinion: Pozanicline was shown to be effective in a pilot study in humans with ADHD, but larger trials were negative. Developing an efficacious therapy is difficult. ADHD is a complex disorder with an unknown cause, and it is unclear, at this time, which qualities from NNR agonists are needed to treat it. It is therefore necessary to develop a more enhanced understanding of the nicotinic cholinergic system and its role in ADHD. Furthermore, new research paradigms may need to be employed to find drugs that are effective in patients with ADHD.     

New drugs for treatment of attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is one of the longest recognised and most common neuropsychiatric disorders of childhood. Recent research indicates that ADHD is most often a lifelong condition associated with significant impairment in multiple domains of functioning. ADHD is a clinical diagnosis made on the basis of history and clinical examination. Current molecular, neuroimaging and neuropsychological studies have greatly elucidated our understanding of the basic science of ADHD. The underlying pathophysiology of ADHD has been theorised to be dysregulation of inhibitory noradrenergic frontocortical activity on dopaminergic striatal structures. Pharmacotherapy is recognised as the most effective component of ADHD treatment, although some role exists for proper educational placement, parent management training and social skills development. Methylphenidate and amphetamine are the current standards in ADHD medication treatment. Other medication classes such as tricyclic antidepressants and certain antihypertensives are also used in off-label therapy. Anticipated improvements in new ADHD medications include the development of extended release delivery systems, improved tolerability, alternative mechanisms of action and enhanced efficacy in treatment refractory cases.     

Pharmacotherapy of attention-deficit hyperactivity disorder in adolescents

Attention-deficit hyperactivity disorder (ADHD) is a common neurobehavioural disorder in children and adolescents, consisting of developmentally inappropriate levels of inattention and/or hyperactivity and impulsivity. The majority of children with ADHD will continue to experience significant ADHD symptoms as teens. ADHD in adolescents can result in significant functional impairment and poorer quality of life. Children and adolescents with ADHD are at higher risk of developing other psychiatric illnesses such as mood, conduct and substance abuse disorders. Stimulants (amphetamines and methylphenidates) and nonstimulants (atomoxetine, guanfacine extended-release (XR) and clonidine XR) have been found to be effective and are approved by the US FDA for the treatment of ADHD in adolescents in the US. Of the agents approved in the US, only guanfacine XR and clonidine XR are not approved in any other countries. There is growing evidence that treatment of ADHD with stimulants reduces the risk of development of other psychiatric co-morbidities, including substance abuse disorders. To date, all FDA-approved stimulants and nonstimulants that have been adequately studied have been demonstrated to be safe and effective in treating ADHD in both children and adolescents. Therefore, clinical decisions used in selecting pharmacotherapy to treat ADHD in children aged 6-12 years can be applied in the adolescent population.     

Animal models of attention-deficit/hyperactivity disorder

Attention-deficit hyperactivity disorder (AD/HD) is a clinically heterogenous disorder including hyperactivity, impulsivity, and inattention. Both psychostimulant and non-psychostimulant drugs such as methylphenidate and atomoxetine, respectively, to modulate catecholeamine neurotransmission are used as current pharmacotherapies for AD/HD. Multiple lines of evidence suggest that genetic factors play major roles in the etiology of AD/HD. meta-Analyses and pooled data analyses have suggested associations between AD/HD and polymorphisms in genes encoding monoamine neurotransmission molecules. There has been considerable research on this disorder using genetic, pharmacological, and neuroimaging approaches, and several animal models of AD/HD such as spontaneously hypertensive rat (SHR), dopamine transporter (DAT) knockout mice, coloboma mutant mouse, and Grin1 mutant mouse have been reported. These animal models are valuable tools for investigating molecular, cellular, and behavioral mechanisms as well as the neural development and circuit mechanisms of AD/HD. Here, we review the recent literature on animal models of AD/HD and discuss their advantages and limitations.     

GRF-induced GH response in attention-deficit hyperactivity disorder

Attention-deficit hyperactivity disorder (ADHD) is a type of disruptive behavior of unknown etiology with a prevalence of 2.5-5% in school-age children. The useful evaluation of the GRF-induced GH response as a marker in some mental disorders led us to study the response of GH to the exogenous administration of GRF (1-29) NH2 (150 micrograms, i.v.) in ADHD children (N = 12, age = 7.78 +/- 1.66 years) and healthy children (N = 6; age = 8.73 +/- 2.24 years) in order to evaluate the functioning of the somatotropinergic system (GRF-SS-GH-SM axis) and using this neuroendocrine test as a potential diagnostic marker and/or a therapeutic predictor in ADHD. While controls (CS) showed a maximum GH response to GRF 15 min after injection (37.15 +/- 29.56 ng/ml; basal GH = 5.49 +/- 4.71 ng/ml), ADHD children (basal GH = 2.28 +/- 1.66 ng/ml) exhibited a lower response with a plateau from 15 (21.32 +/- 10.00 ng/ml) to 60 min (26.48 +/- 23.72 ng/ml). Serum GH levels at 90 (17.23 +/- 14.45 vs. 5.99 +/- 2.82 ng/ml, p less than 0.05) and 120 min (11.89 +/- 8.63 vs. 4.12 +/- 1.66 ng/ml, p less than 0.05) were significantly higher in ADHD than in CS. According to the GRF-induced GH response elicited in ADHD, two different populations of patients can be distinguished; one group with high response of GH (AUC = 3372.21 +/- 1127.61 ng.min/ml) and another group with a hyporeactive GH (AUC = 1567.46 +/- 726.0 ng.min/ml, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Clonidine extended-release: in attention-deficit hyperactivity disorder

Clonidine, an α(2)-adrenergic agonist, is approved in the US as an extended-release (XR) tablet for the treatment of attention-deficit hyperactivity disorder (ADHD) in children and adolescents (aged 6-17 years). In two, randomized, double-blind, multicenter, phase III trials of 8 weeks' duration, clonidine XR improved the symptoms of ADHD in children and adolescents. Significantly greater reductions from baseline in ADHD rating scale IV (ADHD-RS-IV) total scores at week 5 (primary endpoint) were achieved by recipients of clonidine XR 0.2 and 0.4?mg/day monotherapy than by recipients of placebo. When added to patients' normal stimulant regimen, significantly greater reductions from baseline in ADHD-RS-IV total scores at week 5 (primary endpoint) were achieved with a flexible dose of clonidine XR 0.1-0.4?mg/day than with placebo. Symptomatic improvement of ADHD was achieved following 2 weeks' treatment with clonidine XR. In both trials, significantly greater reductions from baseline in ADHD-RS-IV total scores were apparent at week 2 onwards for recipients of clonidine XR than for recipients of placebo. Clonidine XR was generally well tolerated as monotherapy and as adjunctive therapy with stimulant regimens in clinical trials in children and adolescents.     

New drugs for the treatment of attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is the most common neuropsychiatric disorder of childhood. Recent research indicates that ADHD most often persists into adolescence and adulthood, and is associated with impairments in academic, social and occupational functioning. The ADHD diagnosis is based on history and clinical examination. There are no objective laboratory measures for diagnosis. ADHD is largely heritable. Its underlying pathophysiology has been theorised to include dysregulation of inhibitory noradrenergic frontocortical activity on dopaminergic striatal structures. Evidence shows that ADHD is highly responsive to pharmacological treatments resulting in global functional improvements. Although pharmacotherapy is recognised as the most effective treatment, additional components to optimise ADHD management include proper educational placement, parent management training and social skills development. Central nervous system stimulants, specifically methylphenidate and amphetamine, remain first-line pharmacological treatments. Atomoxetine, a selective noradrenergic re-uptake inhibitor, is the first non-stimulant compound to receive FDA approval for paediatric and adult ADHD. Other medication classes, including alpha-agonist antihypertensives, tricyclic antidepressants, other antidepressants such as buproprion, and the wake-promoting agent modafinil, are prescribed in off-label therapy. Ongoing development of new ADHD medications is expected to emphasise alternative and extended-release delivery systems and non-stimulant compounds.     

Hepatic events associated with atomoxetine treatment for attention-deficit hyperactivity disorder

OBJECTIVE: This study describes and assesses potential hepatobiliary events related to atomoxetine therapy, as reported in clinical trials and as spontaneous adverse event reports post-launch in 2002. METHODS: Case reports that contained potential hepatobiliary events were identified by a computerized search of the Eli Lilly and Company atomoxetine spontaneous adverse events and clinical trials databases. All cases were reviewed by at least two company physicians, one with expertise in hepatology, to determine the relevance of the information in respect of potential liver toxicity. RESULTS: Of 7961 paediatric and adult patients treated with atomoxetine in clinical trials, 41 were identified as having hepatobiliary events requiring additional analysis. Most of these events were mild increases in ALT and AST levels. None of these cases met Hy's rule criteria or progressed to liver failure. During the 4 years after market launch, 351 spontaneous reports of adverse events were related to the liver, of which 69 had other explanations unrelated to atomoxetine. Of the remaining 282 cases, 133 contained possible confounding factors (and were deemed to be possibly related), 146 presented too little information to assess, and three suggested atomoxetine as a probable cause of liver injuries. One of the three had a positive rechallenge. All three patients recovered after discontinuation of the drug. CONCLUSIONS: Since the launch of atomoxetine therapy, three spontaneously reported cases of reversible drug-induced liver injury were deemed probably related to it. Atomoxetine should be discontinued in patients with jaundice or laboratory evidence of liver injury and should not be restarted.     

Guanfacine extended-release for attention-deficit/hyperactivity disorder (ADHD)

Importance of the field: Guanfacine extended-release (GXR) is a non-stimulant approved in the US for treatment of attention deficit/hyperactivity disorder (ADHD). GXR is a ‘first in class’ α_2A-adrenoceptor agonist reformulated to optimize efficacy. GXR enters a rapidly growing but crowded ADHD market as an alternative not only to psychostimulants but also to atomoxetine.

Areas covered in this review: Pharmacodynamics, pharmacokinetics, clinical efficacy and safety of GXR are covered based on a literature review (MEDLINE and EMBASE) from 1980 to 2010. Two large pivotal controlled trials are reviewed along with companion safety studies over 24 months. Collateral studies in ADHD children with oppositional symptoms and combination use of GXR in psychostimulant partial-responders are featured.

What the reader will gain: Novel aspects of apparent GXR mechanism of action may complement existing treatments. Study evidence indicates that GXR is a well-tolerated and effective treatment for children and adolescents with ADHD, and appears efficacious to reduce oppositional symptoms in children with these complicating features. The GXR safety database reflects mild and asymptomatic decreases in both blood pressure and heart rate throughout, with most adverse events being somnolence-related and time-limited.

Take home message: This review of GXR will allow the reader to determine the place for GXR in the ADHD treatment landscape.     

Dexmethylphenidate extended release: in attention-deficit hyperactivity disorder

Dexmethylphenidate extended release (XR) is an orally administered, bimodal release, capsule formulation of the active d-enantiomer of methylphenidate (MPH), which inhibits dopamine and norepinephrine (noradrenaline) reuptake to increase their concentration in the extraneuronal space. A single dose of dexmethylphenidate XR mimics the pharmacokinetic profile of two doses of dexmethylphenidate immediate-release formulation administered 4 hours apart, albeit with less fluctuation in plasma concentration. Once-daily dexmethylphenidate XR was more effective than placebo in reducing attention-deficit hyperactivity disorder (ADHD) symptom scores in children, adolescents and adults with ADHD in four randomised, double-blind, placebo-controlled trials of up to 7 weeks' duration. In crossover trials in children (aged 6-12 years), dexmethylphenidate XR 20 mg/day reduced mean ADHD symptom scores 1 hour after administration (by 43% in one trial) and was significantly better than placebo for up to 12 hours. Dexmethylphenidate XR 5-30 mg/day reduced mean ADHD symptom scores by 49%, while scores declined by 16% with placebo in a 7-week trial in children and adolescents (aged 6-17 years). Dexmethylphenidate XR 20, 30 or 40 mg/day reduced ADHD symptom scores by 36-46% versus a 21% reduction with placebo in a 5-week trial in adults (aged 18-60 years). Dexmethylphenidate XR was generally well tolerated in children, adolescents and adults with ADHD, with an adverse-event profile typical of MPH.